The defining feature of chronic obstructive pulmonary disease (COPD) is irreversible airflow limitation measured during forced expiration. This results from a varying combination of increased airflow resistance in the small airways and decreased elastic recoil due to emphysematous destruction of lung tissue. We recently showed that significant obstruction of the small airways is present in the lungs of patients with advanced emphysema and that the inflammatory response in the peripheral lung tissue correlates with the severity of COPD as gauged by the GOLD classification scheme. Quantitative analysis of the inflammatory response found strong correlation with the level of lung infiltration by CD8+ T cells, B cells, and macrophages and suggested that these cell types may specially serve to drive the COPD phenotype. Using CT and 3He magnetic resonance imaging (3He MRI) to quantitatively assess regional differences in small airway obstruction and emphysematous destruction in severe COPD, our imaging group has found that regions of mild to moderate disease are found adjacent to sites of severe destruction or obstructive disease even in patients with GOLD 4-stage disease. We hypothesize that the different levels of lesion severity represent different stages in the pathogenesis of the lesions. Our active lung transplantation program, expertise in new imaging technologies and the ability to conduct quantitative analysis of the inflammatory response and tissue remodeling afford a unique opportunity to construct new criteria for assessment of COPD patients. We propose to investigate the pathogenesis of GOLD 4-stage COPD in patients awaiting lung transplant with the following Specific Aims: 1) To test the hypothesis that there is progression in both extent and severity of the inflammatory immune process in regions affected by moderate to severe degrees of emphysema and small airway disease, using morphologic analysis and quantitative immunopathology to characterize the inflammatory immune process. 2) To noninvasively quantify the regional extent and severity of disease separately in subjects with severe COPD using 3He MRI and high-resolution CT imaging. 3) To validate the in-vivo and ex-vivo imaging results in Aim II against the histology in Aim I in order to develop a new approach to quantifying both the extent and severity of emphysema and small airways disease within the lungs of individual patients with COPD.